A Fine Chemical Version of Chernobyl?

A study by Dr. Joakim Larsson et al (1) in September 2007 about fine chemical pollution in Patancheru, India has suddenly become an eye of a storm in India (2, 3, 4, 5, 6, 7). There are denials of the scientific study as it exposes weak links. For the long term, these issues have to be addressed. If the problems are not corrected, the area could be equated to Chernobyl of the fine/specialty chemicals and pharmaceutical industries. There is a solution out of this quandary.

Solution touches the heart of manufacture of active pharmaceutical ingredients (API) and their subsequent formulations. Using Professor Larsson’s study, I have presented potential scenarios for Patancheru’s problems and a solution (8). The process yield can be improved. Effort is needed. Depending on total ciprofloxacin capacity, which is a quinolone, the companies can collectively reduce out fall by 30-60 kg/day. This might not look a big number but based on total daily production this is big. Based on toxicity this is significant. Similar savings can be achieved on other quinolones and other drugs.

In the recent brouhaha ciprofloxacin has been identified as the culprit. Actually, the problem is much bigger. There are other quinolones and APIs being produced and formulated by many companies in Hyderabad and the vicinity. Not only are there producers of these products, there are suppliers of the necessary raw materials for these products in the area. Effluent from these chemical plants also discharges in water bodies in the area. Even if the effluent meets the established local standards of chemical discharge, no one has established the toxicity of every chemical that is trickling into the ecosystem.

If we want to salvage the Patancheru eco-system, we should establish toxicity levels of associated chemicals and use them rather than the current chemical limits to control effluent. We have to recognize that every active pharmaceutical ingredient is toxic to varying degree and their toxicity kills the disease causing bacteria. The lessons learnt from Patancheru could be applied globally.

Why do we have a problem?

High levels of chemicals entering the effluent treatment plant point to inefficient manufacturing technology and low yields of the manufacturing process. Questions should be asked that why we have a problem and if the yields could be improved to reduce the effluent load, why it has not been improved. There is a simple answer to these questions and it encompasses the following.

Since high profit margins are made with the existing processes, there is no incentive to improve them. If the companies can meet the local water, solid and air effluent standards, there is no need to worry about the eco-toxic or toxicity effect, as there are no standards.

The current process with their current low yield produces a chemical that meets a certain impurity profile that has been approved by the drug regulatory agencies. If the yield is improved, the producer should be able to reduce the chemical discharge load. This improvement could change the impurity profile of the active ingredient. Under the current regulatory laws of various countries (9), the producer might have to re-qualify the higher drug produced by an improved process for its performance and efficacy. This is an expensive and long drawn process. In addition, processes might have to re-audited. No one wants to invest any money in this effort.

Since the current processes are not efficient, the product quality is controlled at every intermediate step and this is called quality by analysis. Reasons of low yield i.e. high amount of chemicals in the effluent are that the processes are not completely understood. Lack of complete process understanding and control can result is a product that is made on day 100 of one year and day 200 of the same year to be slightly different or might not meet specifications. If the product does not meet the defined specifications that have been filed and approved, the product could be reworked or disposed. These products and their intermediates are equally or more toxic and could leach out in the soil and water. Quality by analysis insures high quality and this is expensive. These costs can be contained or eliminated if we understand have repeatable processes.

Problems identified by Professor Larsson do exist in many areas of the world where active pharmaceutical ingredients are produced. However, they have not been studied. I am sure we will find similar problems.

The Solution

The only solution out of the dilemma in Hyderabad is to improve the process manufacturing technologies. This has to be done for the short and the long haul. If the manufacturing processes can be improved, depending on the total capacity of the quinolone plants in Patancheru area, significant quantities of ciprofloxacin instead of going to waste water and solid disposal can be recovered as a product. It will make a big impact on the local ecosystem. Ciprofloxacin is one of the many quinolones being produced in Hyderabad. The plants producing ciprofloxacin also produce other quinolones. In addition, we have to recognize that there are ancillary plants in the area that produce raw materials for these products. Their effluent is part of the wastewater and solid sludge system. There are many other actives produced in the area and their levels have not been tested.

Manufacturing technology improvement is the only solution to reduce chemicals in the eco-system. Drug regulatory agencies have lately suggested that manufacturing improvements should be done. Formulators and producers of actives pharmaceutical ingredients claim that there are hurdles of bureaucracy and insufficient ROI. I have difficulty believing that. Meeting chemical effluent standards at Patancheru would be the first step. Unless effluent toxicity standards are established, not much will change. Intervention is needed to rationalize toxicity and address the “Patancheru problem”. We have to maximize our effort to improve manufacturing technologies.